Carbohydrates represent a particularly enticing and important challenge to the understanding of molecular recognition (Davis et al., In Functional Synthetic Receptors, Schrader et al., eds., Wiley-VCH, Weinheim, p. 47 (2005)). In addition to their role in addressing the fundamental problem of understanding binding and selectivity, novel carbohydrate receptors have significant potential as tools in the rapidly evolving field of glycomics (Raman et al., Nature Meth. 2:817-824 (2005); Ratner et al., Chem. BioChem. 5:1375-1383 (2004)), as components of sensing systems for isolated sugars (Zhang et al., Org. Lett. 8:1649-1652 (2006); Gao et al., Tetrahedron 61:9111-9117 (2005); Yoon et al., J. Am. Chem. Soc. 114:5874-5875 (1992); Shinkai et al., Biosens. Bioelectron. 20:1250-1259 (2004)) and for pathogens (Chan et al., J. Am. Chem. Soc. 123:11797-11798 (2001)), and as leads for the development of new therapeutic agents (Miller et al., J. Med. Chem. 48:2589-2599 (2005); Ding et al., J. Am. Chem. Soc. 126:13642-13648 (2004)). However, as has been noted by others, the design of organic receptors able to bind simple, non-ionic sugars via noncovalent interactions is a daunting task (Wiskur et al., Chem. Eur. J. 10:3792-3804 (2004)). This is particularly true when the goal is binding sugars in protonated solvents, since the solute looks much like ordered solvent.
A number of synthesis schemes have been described for various tri-podal receptors. These include a four-step process for the preparation of a tricatecholic-benzene receptor for carbohydrates (i.e., from 1,3,5-triethylbenzene and pyrogallol) (Cacciarini et al., J. Org. Chem., 72(10):3933-3936 (2007); a multi-step process for preparation of the tri-imidazolinyl-benzene tri-podal receptors (i.e., preparation of intermediate 1-aminomethyl-2,4,6-triethyl-3,5-(N-(imidazoline-2-yl-aminomethyl)benzene from 2,4,6-triethyl-1,3,5-tri(aminomethyl)benzene, and then reaction of the intermediate with (2-formylphenyl)boronic acid followed by reduction) (Lavigne et al., Angew. Chem. Int. Ed. 38:3666-3669 (1999)); and a multi-step process for the formation of tri-pyrazolyl benzene tri-podal receptors (i.e., via reaction of the sodium anion of 3,5-dimethyl pyrazole with 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene) (Chin et al., Angew. Chem. Int. Ed. 38:2756-2759 (1999)). For tri-podal receptors lacking the benzene core, such as the tyrosine-based receptor described in Tajc et al., J. Am. Chem. Soc. 128:2532-2533 (2006), a multi-step process is described for the reduction of cyclohexane 1,3,5-tricarboxylic acid to the trimethanol intermediate, and reaction of the trimethanol intermediate with N-Boc (or N-Fmoc) tyrosine under standard coupling conditions, followed by deprotection.
It would be desirable to identify a simpler synthesis scheme that can be used to develop novel tripodal receptors, which can then be used for carbohydrate and other macromolecular recognition.
Tripodal receptors have been a mainstay of the molecular recognition field (Lavigne et al., Angew. Chem. Int. Ed. 38:3666-3669 (1999); Chin et al., Angew. Chem. Int. Ed. 38:2756-2759 (1999)). In the realm of noncovalent carbohydrate recognition, tripodal receptors based on arenes have been explored extensively by the Mazik group, who demonstrated that aromatic compounds incorporating aminopyridine side chains (Mazik et al., Angew. Chem. Int. Ed. 39:551-554 (2000)) are able to bind alkylpyranosides as 1:1 and 2:1 complexes in chloroform with substantial affinity and selectivity (Mazik et al., Org. Lett. 8:855-858 (2006)). Other notable examples of arene-based tripodal carbohydrate receptors have been described by the Roelens (Vacca et al., J. Am. Chem. Soc. 126:16456-16465 (2004)), Abe (Abe et al., Org. Lett. 7:59-61 (2005)), and Schmuck (Schmuck et al., Org. Lett. 7:3517-3520 (2005)) groups, who studied hexasubstituted benzene-based tripodal receptors incorporating urea, phenol, and guanidinium substituents, respectively. Despite these major achievements, and elegant structures such as the carbohydrate-binding cage structure developed by Davis and coworkers (Velasco et al., Org. Biomol. Chem. 2:645-647 (2004)), binding in protic solvent remains an essentially unsolved problem.
Several of the present inventors demonstrated prior success with the use of a cycloalkane oligomer as a conformational control element in the development of receptors for lipid A (Hubbard et al., J. Am. Chem. Soc. 123:5810-5811 (2001); Gareiss et al., Eur. J. Org. Chem. 53 (2007)). While highly substituted cyclohexanes, for example Kemp's Triacid, have proven useful as components in molecular recognition systems (Kocis et al., Tetrahedron Lett. 36:6623-6626 (1995); Rebek et al., J. Am. Chem. Soc. 109:2426-2431 (1987); Kemp et al., J. Org. Chem. 46:5140-5143 (1981)), receptors based on a simple cis-1,3,5-trisubstituted cyclohexane core are less well known (Tajc et al., J. Am. Chem. Soc. 128:2532-2533 (2006); Ryu et al., Bull Kor. Chem. Soc. 22:1293-1294 (2001)).
The present invention is directed to overcoming these and other deficiencies in the art.